Characterisation of GNB1L, a novel gene on chromosome 22qll, implicated in schizophrenia and autism

• Main Author: Riaz, Zahra
• Format: Dissertation
• Language: English
• Published: St George's, University of London 2015

GNB1L is a novel gene located in the 22ql1.2 DS critical region. It has been genetically implicated in the psychiatric subtypes of 22qll.2 DS including schizophrenia and autism. Previous research suggests that GNB1L is important in the brain, but has shed no light on a potential function. The aim of this current investigation was to begin characterising Gnbll and its role in the brain. This was in order to elucidate a function of GNB1L, and therefore identify a possible pathogenic mechanism in which it may contribute to psychiatric subtypes of22ql1.2 DS. Gnbll+/ - lacZ gene-trap mice demonstrate deficits in pre pulse inhibition of the startle response, a characteristic of psychosis in humans. In these mice, strong, region-specific, Gnbl1 expression was observed in embryonic and postnatal brain stages of development. Prominent regions of expression included the cerebral cortex, hippocampus, and cerebellum. There was consistent expression in these regions, indicating that Gnbll may play a role in their development and function. A brain specific yeast two-hybrid assay linked Gnbll to proteins with known brain specific functions. From this assay, and a previous yeast two-hybrid, a review of Gnbll protein interactions revealed many links to the canonical Wnt signalling pathway. This pathway is essential for regulation of key events in neurodevelopment, and plays a significant role in the adult brain. A GST pull-down assay confirmed Gnbll interaction with Hipkl, a regulator of the Wnt signalling pathway, which has importance in the developing cerebral cortex. Investigations in vitro revealed that both HIPKl and GNB1L negatively regulate Wnt target gene expression through inhibition of ~ catenin activity. Further assays found potential inhibitory mechanisms of GNB1L and HIPKl in the pathway. Disrupted Wnt signalling has been previously implicated in pathophysiology of psychiatric disorders, and components of the pathway are commonly used as drug targets for treatment of psychosis. This thesis provides a novel functional role for GNB1L, and further implicates deficits in Wnt signalling as a potential pathological mechanism of psychosis in 22ql1.2 DS patients. This may lead to better diagnosis and treatment of these patients in the future.